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Title: FXR agonist activity of conformationally constrained analogs of GW 4064

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. (GSKNC)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1149624
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorg. Med. Chem. Lett.; Journal Volume: 19; Journal Issue: (16) ; 08, 2009
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Akwabi-Ameyaw, Adwoa, Bass, Jonathan Y., Caldwell, Richard D., Caravella, Justin A., Chen, Lihong, Creech, Katrina L., Deaton, David N., Madauss, Kevin P., Marr, Harry B., McFadyen, Robert B., Miller, Aaron B., Navas, III, Frank, Parks, Derek J., Spearing, Paul K., Todd, Dan, Williams, Shawn P., and Wisely, G. Bruce. FXR agonist activity of conformationally constrained analogs of GW 4064. United States: N. p., 2014. Web. doi:10.1016/j.bmcl.2009.06.062.
Akwabi-Ameyaw, Adwoa, Bass, Jonathan Y., Caldwell, Richard D., Caravella, Justin A., Chen, Lihong, Creech, Katrina L., Deaton, David N., Madauss, Kevin P., Marr, Harry B., McFadyen, Robert B., Miller, Aaron B., Navas, III, Frank, Parks, Derek J., Spearing, Paul K., Todd, Dan, Williams, Shawn P., & Wisely, G. Bruce. FXR agonist activity of conformationally constrained analogs of GW 4064. United States. doi:10.1016/j.bmcl.2009.06.062.
Akwabi-Ameyaw, Adwoa, Bass, Jonathan Y., Caldwell, Richard D., Caravella, Justin A., Chen, Lihong, Creech, Katrina L., Deaton, David N., Madauss, Kevin P., Marr, Harry B., McFadyen, Robert B., Miller, Aaron B., Navas, III, Frank, Parks, Derek J., Spearing, Paul K., Todd, Dan, Williams, Shawn P., and Wisely, G. Bruce. Tue . "FXR agonist activity of conformationally constrained analogs of GW 4064". United States. doi:10.1016/j.bmcl.2009.06.062.
@article{osti_1149624,
title = {FXR agonist activity of conformationally constrained analogs of GW 4064},
author = {Akwabi-Ameyaw, Adwoa and Bass, Jonathan Y. and Caldwell, Richard D. and Caravella, Justin A. and Chen, Lihong and Creech, Katrina L. and Deaton, David N. and Madauss, Kevin P. and Marr, Harry B. and McFadyen, Robert B. and Miller, Aaron B. and Navas, III, Frank and Parks, Derek J. and Spearing, Paul K. and Todd, Dan and Williams, Shawn P. and Wisely, G. Bruce},
abstractNote = {},
doi = {10.1016/j.bmcl.2009.06.062},
journal = {Bioorg. Med. Chem. Lett.},
number = (16) ; 08, 2009,
volume = 19,
place = {United States},
year = {Tue Aug 19 00:00:00 EDT 2014},
month = {Tue Aug 19 00:00:00 EDT 2014}
}
  • Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
  • To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
  • Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
  • Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10 K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to altermore » CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs. - Highlights: • A subset of Tox21 chemicals was investigated for FXR antagonism. • In vitro and computational approaches were used to evaluate FXR antagonists. • Chlorophacinone and ivermectin had distinct patterns in modulating FXR activity.« less
  • The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-{angstrom} resolution. The steroid ring system ofmore » MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.« less